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J Examination of the Effects of Certain Acute Environmental Exposures on Future Respiratory Health Consequences

David H. Wegman, M.D., M.S.*

I have been asked to address two primary issues: Can human exposures to nitrogen mustard gases over relatively brief intervals eventually lead to chronic nonmalignant pulmonary effects? Can such effects be of a degree sufficiently severe to disable them? In both clinical and public health terms these issues can be restructured as follows: 1) Does the occurrence of an acute pulmonary reaction identify an individual at risk for long-term respiratory sequelae? 2) If so, can the probability or degree of damage be predicted from the magnitude of the acute response? 3) What assurance is there that the absence of an acute pulmonary reaction identifies individuals who will not develop long-term sequelae?

To begin, it is recognized that little structured study of the mustards has occurred among human populations acutely overexposed. Without attempting to estimate the relative importance of the different respiratory conditions or to estimate the dose levels necessary to cause each, a variety of conditions have been noted. Low dose inhalation exposure of mustard gas has been noted to result in chest tightness while higher doses have resulted in sneezing, lacrimation, rhinorrhea, nasal bleeding, sore throat, hoarseness and cough.1 The WHO has reported the pulmonary effects in Iranian patients exposed during the Iran-Iraq war.2,3 Acute effects included: (2-4 hrs) chest tightness, sneezing, lacri-

*  

University of Massachusetts at Lowell. Prepared for the Institute of Medicine's Committee to Survey the Health Effects of Mustard Gas and Lewisite.



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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite J Examination of the Effects of Certain Acute Environmental Exposures on Future Respiratory Health Consequences David H. Wegman, M.D., M.S.* I have been asked to address two primary issues: Can human exposures to nitrogen mustard gases over relatively brief intervals eventually lead to chronic nonmalignant pulmonary effects? Can such effects be of a degree sufficiently severe to disable them? In both clinical and public health terms these issues can be restructured as follows: 1) Does the occurrence of an acute pulmonary reaction identify an individual at risk for long-term respiratory sequelae? 2) If so, can the probability or degree of damage be predicted from the magnitude of the acute response? 3) What assurance is there that the absence of an acute pulmonary reaction identifies individuals who will not develop long-term sequelae? To begin, it is recognized that little structured study of the mustards has occurred among human populations acutely overexposed. Without attempting to estimate the relative importance of the different respiratory conditions or to estimate the dose levels necessary to cause each, a variety of conditions have been noted. Low dose inhalation exposure of mustard gas has been noted to result in chest tightness while higher doses have resulted in sneezing, lacrimation, rhinorrhea, nasal bleeding, sore throat, hoarseness and cough.1 The WHO has reported the pulmonary effects in Iranian patients exposed during the Iran-Iraq war.2,3 Acute effects included: (2-4 hrs) chest tightness, sneezing, lacri- *   University of Massachusetts at Lowell. Prepared for the Institute of Medicine's Committee to Survey the Health Effects of Mustard Gas and Lewisite.

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite mation, rhinorrhea, epistaxis, hacking cough; (4-16 hrs) sinus pain, severe epistaxis; (16-24 hrs) severe cough; (24-48 hrs) severe dyspnea, pulmonary edema; (48-72 hrs) bronchopneumonia. Delayed effects measured after two years included: chronic bronchitis, asthma, rhinopharyngitis, tracheobronchitis, laryngitis, recurrent pneumonia and bronchiectasis. In summary, then, overexposure to nitrogen mustards has caused both airway reactions and parenchymal damage with increased risk of pulmonary infection. Since the respiratory conditions described in instances of severe overexposure to nitrogen mustards have been both acute and chronic, there is evidence that some level of exposure to these agents can cause both severe acute and chronic respiratory disease. However, there is little evidence available on the effects of lower level acute exposure and none apparently on brief exposures which are not too excessive. In the absence of follow-up studies that directly address the question, much of the exploration must involve examining indirect evidence from the study of compounds which might behave similarly. In order to evaluate the respiratory health risk associated with repeated brief overexposures at lower levels, review of indirect evidence will focus on examining the link between acute and chronic respiratory responses to such agents. One central difficulty in examining this question is the absence of knowledge about the early stages of environmentally related pulmonary diseases coupled with almost no knowledge on the natural (longitudinal) evolution of the clinical conditions. Thus there is little to guide us in what is the appropriate disease model and what pattern(s) of exposure are relevant to disease etiology. REVIEW OF AGENTS CAUSING ACUTE AND CHRONIC RESPIRATORY EFFECTS The following agents have been selected to illustrate the range of exposure-effect relationships that may be relevant to the effects of the mustards. It will be noted that the agents selected have been shown to result in (to cause) a mix of respiratory conditions: Exposures to irritant gases (chlorine, SO2, combustion products); exposures to materials of plant origin (cotton); exposures to chemicals (isocyanates); and exposures to inorganic dusts (silica, beryllium, asbestos). Chlorine Since chlorine gas is such an irritating substance, there are a number of reports of overexposures with documented acute respiratory effects.

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite These provide clear evidence of severe acute respiratory damage with intensity commensurate with the exposure level and duration.4,5 Several investigators have attempted to follow subjects who have experienced acute symptomatic effects to determine whether these either persist or progress. To date, most of the reports of accidental overexposures suggest that individuals return to normal.6,7 A few reports have documented persistent obstructive or restrictive effects in follow-up of 1, 3 and 12 years.8,9,10 In one case report a previously healthy individual suffered onset of irreversible and debilitating asthma following a single overexposure.11 In all instances there has been an absence of pre-accident health assessments so whatever residual effects are present at from 6 months to 13 years later cannot be attributed to the acute accidental exposure alone. In contrast to these studies of single acute overexposure episodes, there are two populations of workers occupationally exposed to chlorine gas where the importance of accidental gassings has been evaluated. In a cross-sectional study of chlorine gas plant workers, 55 of 139 were reported to have experienced accidental overexposures against a background of less than 1 ppm.12 Of those overexposed, only three showed significant impairment which might only represent statistical variability in the population. Overall there was, however, evidence of persistent minor airflow abnormalities. In a more detailed study of pulpmill workers, evidence of an effect of gassings was presented.13 Although several irritant gases were present in the pulpmill, chlorine was the dominant irritant exposure. Overall the pulpmill workers had more symptoms but no pulmonary function differences compared to a control working population. However, those with gassings had all the excess of symptoms and had more airflow obstruction compared with the other pulpmill workers. Evidence of healthy worker selection was also noted as likely to have decreased the strength of the findings. This population had been studied seven years previously by the same investigators. Those workers who had experienced chlorine gassings once or twice during the study interval were compared to the remainder. 14 For those whose gassing resulted in their seeking first-aid assistance at the time, there was evidence that respiratory symptoms and airflow obstruction had progressed when 1988 measures were compared to ones taken in 1981. These effects were present after controlling for cigarette smoking. In summary, there is clear evidence of acute respiratory effects from chlorine exposures which include both acute bronchitis and airway obstruction as well as inflammatory bronchoconstriction (RADS). There is also evidence for a chronic effect from exposure to chlorine. The relationship of acute respiratory effects to chronic ones is also present,

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite although the evidence is less clear in the absence of continued very low level exposure to chlorine gas independent of the overexposure. In at least one case a single exposure in a previously asymptomatic individual resulted in a debilitating chronic condition. There are no studies that followed individuals acutely overexposed but not acutely symptomatic to determine whether chronic effects were likely to develop. Sulfur Dioxide Sulfur dioxide is an agent with irritant potential equal to that of chlorine. Both agents are moderately soluble in water, are likely to result in inflammatory bronchoconstriction with the amount of upper respiratory tract irritation dependent on exposure level. Sulfur dioxide also shows clear evidence of acute respiratory effects related to short exposures. These include evidence of bronchial constriction and chest tightness.4 Studies of chronic respiratory effects associated with sulfur dioxide exposures have yielded mixed results. However, those which included individual assessment or assignment of SO2 exposure have demonstrated accelerated loss of pulmonary function overall as well as among those with poorer baseline function.15,16 There are, however, some important differences between the two irritants when considering the impact of acute overexposures. As with chlorine, the primary respiratory response seen as a result of accidental overexposure is obstructive and includes both pulmonary function and symptoms of productive cough, wheeze and chest tightness. However, whereas those who experience single accidental exposures to chlorine generally recover most of their pulmonary function losses, those similarly overexposed to sulfur dioxide almost always do not. In three studies where acute overexposed subjects were followed for 4 months to 4 years all but one showed evidence of functional abnormality (predominantly obstructive in nature).17,18,19 In summary then, there is clear evidence that sulfur dioxide can cause acute respiratory effects and it is likely that lower level exposures over time result in chronic obstructive abnormalities. Single overexposure episodes which produce acute respiratory symptoms appear to cause irreversible damage. No follow-up studies of those acutely overexposed but not symptomatic have been reported. Miscellaneous Irritants A variety of reports have been published where single accidents or episodes have resulted in overexposure to many different irritant

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite agents. In several of these there has been an attempt to follow-up those who were adversely affected in order to determine the persistence of any immediate abnormalities. Prominent among these has been the examination of firefighters who have been acutely exposed to a variety of combustion products.20 As might be expected, in a number of the reports only transient pulmonary function changes have occurred.21,22 In cases where fires involved polyvinyl chloride,23 isocyanates24 or ''plastics"25 there was evidence of persistent effects ranging from increased symptoms to progressive fatal asthma. A follow-up of survivors of a subway fire suggested persistence of small airway damage and respiratory symptoms at six months and two years.26 In 1985 Brooks, et al., described the clinical condition of reactive airways dysfunction syndrome (RADS).27 The condition is asthma-like but differs from occupational asthma because of an absence of a preceding period for sensitization to occur and the onset of illness after a single overexposure. A single exposure to a glacial acetic acid spill was carefully studied and the relative odds of developing RADS was estimated to be as large as 10 for the highest exposure group. 28 Although no general estimate is available of the probability that RADS will follow from a single high irritant exposure, the number of agents which have been reported is quite varied and includes uranium hexafluoride, hydrazine, heated acids, perchlorethylene and toluene diisocyanate.27,29,30 The severe disability associated with some of these episodes is disturbing. In summary, a number of specific agents as well as poorly described irritant exposures have been shown to cause long-term disability and even death after a single severe overexposure. The suggestion is that any severe exposure to a wide variety of respiratory irritants has a reasonable likelihood of producing serious long-term effects on the respiratory system. The exposure circumstances described in this section did not lead to evaluation of asymptomatic exposed individuals. Therefore, the effects of exposures high enough to cause disability in those who were symptomatic do not directly address the question of chronic effects in the absence of acute illness. Cotton Dust In 1956, Schilling published a summary of descriptive studies which elegantly characterized the persisting risk of disease among cotton textile workers.31 It was Schilling who also was responsible for the development of the symptom score which still best describes the acute symptom complex—ranging from occasional Monday morning chest

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite tightness to chest tightness persisting throughout the workweek but remitting over a weekend. Ample evidence exists to show  the relationship of acute chest tightness, cough and dyspnea related to cotton dust exposure.32,33,34 The classic Monday morning chest tightness has been shown to be dose related35 and to increase with increasing duration of employment.36 Reports of prevalence of the syndrome have varied to levels as high as 50 percent.37 The relationship of these striking acute symptoms to pulmonary function changes has not been well established. Cotton textile workers do show dust-related cross-shift loss in pulmonary function but the relationship of this change to byssinosis has been variable.38,39,40 As suggested in a recent report on the effects of exposures to endotoxin in cotton dust among human volunteers, this problem may be resolved as better characterization of the actual agent evolves.41 In the few efforts to examine the persistence of the acute symptoms in affected workers, studies have shown remission in some of those still exposed42,43 and persistence among those who have been removed from exposure.44 To date there remains no consensus for the mechanism of the acute symptoms related to cotton dust exposures. Although the symptoms are similar to asthma for many of those affected, the dose-response relationship and the absence of clear evidence of immunogenesis have led this acute condition to be classified as a pharmacologic bronchoconstriction. 45 The presence of a chronic effect of cotton dust on respiratory health has been debated for a number of years. There is, however, mounting evidence that such effects do occur. Early mortality studies31 which indicated excess respiratory deaths have not always been confirmed. 46,47 However, the earlier studies were among more highly exposed workers and mortality analysis is generally a very imprecise measure of chronic respiratory disease. A number of studies, both cross-sectional and longitudinal, have examined the effect of cotton textile employment on pulmonary function. Many of the cross-sectional studies have shown lower function in cotton workers,33,39,48,49,50 but inconsistent findings have been reported for the relationship of the lower function to duration of employment35,36 and current dust exposures.33,48 One study did show a relationship to a dust index.32 The longitudinal studies have consistently shown greater loss of FEV1, among cotton textile workers.22,36,38,42,51 In only one of those with under three years follow-up was an association of function loss with duration noted.9 In the three with five or more years, despite methodologic flaws there was not only lower function in the cotton workers but

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite lower function in those who reported byssinosis.16,49 In the most recent one a relationship to job category and dose was described. 51 Although there remains controversy over the presence of a chronic respiratory effect from cotton dust exposures, the mounting evidence appears to lead to the acceptance of such an effect. If the evidence reviewed is accepted then there is substantial support for a relationship of the acute respiratory syndrome to the various chronic effects. These include the accelerated loss of function among byssinotics, 49 the increased prevalence of chronic bronchitis among byssinotics, 36,39,42,52 and the recent identification of a relationship between cross-shift and five year change in FEV1 in Chinese cotton textile workers.53 In summary, exposure to cotton dust or components of the dust has been noted to cause 1) acute effects represented by both a disabling acute respiratory syndrome (byssinosis) and a cross-shift decrement in FEV1, and 2) chronic effects represented by both accelerated annual decrements in FEV1 and chronic bronchitis. The acute syndrome does not necessarily remit on removal from exposure and there is a growing body of evidence to suggest a relationship between the acute effects and chronic airflow limitation. There is evidence that short-term exposures result in acute effects41,54 but none for whether such exposures, with or without an acute response, ultimately lead to chronic effects. Isocyanates These reactive chemical agents have been reported to cause a wide range of nonmalignant respiratory health effects although there are substantial differences in the proportion of the population at risk for each.55 In 1951, case reports of isocyanate-related pulmonary effects called attention to a new occupational asthma.56 Sensitization was reported to occur as early as after only one high exposure,57 but onset could also be delayed for a number of years after first exposure.58,59 Unlike with high molecular weight agents which cause occupational asthma, however, further study of isocyanate asthma cases showed that measurable IgE and airway hyperreactivity was not invariably an essential feature.55,60,61 The course of isocyanate asthma includes the fact that as many as half of seriously affected workers who leave work do not recover.62,63,64 Although it was not initially expected, continued investigation of the effects of work exposure to isocyanates revealed evidence of a number of respiratory effects other than asthma which were important and a series of epidemiologic studies ensued. There is good evidence that high levels of exposure are associated with chemical bronchitis 65 and, recently, with reactive airway dysfunction syndrome.66 Independent of asthma or acute response to serious overexposures,

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite there are well-documented acute and chronic non-specific airway effects from isocyanate exposures. Peters' studied workers exposed to very low levels of TDI. His work demonstrated significant change in FEV1 over the workshift.67 A three year prospective study of these same workers demonstrated the losses were not just acute; exposed workers experienced accelerated losses over three years and there appeared to be a correlation between the magnitude of cross-workshift change and the accelerated functional loss.68,69 My own work provided preliminary information on the relationship of acute and chronic losses to exposure level and that the effects persisted after controlling for cigarette smoking.70,71 Epidemiology studies have also provided a preliminary estimate of a no-effect level72. Work by Weill and his colleagues, in a prospective study of a new plant confirmed the broad population dose-related effects of chronic TDI exposure while directly accounting for healthy worker selection. 73,74 Their work raised the possibility that peak exposures might be important not only for asthma74 but for the non-asthma related chronic losses as well. These epidemiologic studies provided sufficient evidence that TDI was not a problem  for only a small population of sensitized workers, but that the agent was a risk for all TDI workers. Finally no epidemiologic studies have yet examined the importance of the case reports of hypersensitivity pneumonitis as an exposure consequence.55 As these are being reported with increasing frequency their relative importance as a risk from this chemical exposure is an important priority to determine. In summary, isocyanates (a series of small molecular weight chemical compounds) have been noted to cause 1) several acute conditions: chemical bronchitis, allergic bronchoconstriction (after short-term high exposures as well as following longer-term lower exposures), and to cause large dose-related cross-shift loss in FEV1; and 2) chronic respiratory effects including accelerated loss in pulmonary function over several years (suggesting the development of chronic airway limitation) and irreversible asthma. There is also evidence that the acute effects are related to the chronic effects both as asthma that does not remit and as cross-shift loss which is related to the rate of subsequent annual loss. Finally, there is evidence that short-term exposures can cause acute responses that are irreversible and progressive, but there is no evidence, either way, as to whether short-term exposures without acute response result in irreversible respiratory effects. Notes on Selected Inorganic Agents Beryllium exposures have been associated with both acute and chronic pulmonary disease.75 Both acute and chronic conditions have

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite been shown to be disabling. Relevant to the questions being considered here is that exposures in one instance as brief as one week and in several instances occurring for less than 10 weeks have resulted in disease certified for inclusion in the Beryllium Registry established at the Massachusetts General Hospital.76 Silica exposures are generally considered important only for chronic disease. There is, however, the condition of acute silicosis caused by relatively short-term high intensity exposures to very fine silica particulate.77 Exposures as brief as six months have been associated with acute silicosis. But even in the absence of such severe overexposures and acute clinical disease, there is evidence that even low level exposures not associated with clinical symptoms or chest X-ray abnormality can result in irreversible pathology.78 Asbestos exposures similarly are noted for causing chronic respiratory illness as well as cancer. Brief high exposures are not recognized to cause respiratory complaints. However, brief exposures (on average less than four years) have been associated with increased respiratory symptoms and decreased vital capacity.79 THE FUNDAMENTAL QUESTION Narrowly Structured For an acute exposure (intense but over only a short interval) to have a causal association with subsequent respiratory disease conditions, must the exposure cause acute irreversible and progressive damage evidence by acute clinical illness or, at minimum, objective changes in lung parameters or severe subjective symptoms? Alternative Broadly Structured For an acute exposure (intense but over only a short interval) to have a causal association with subsequent respiratory disease conditions, either the exposure must cause acute irreversible (and possibly progressive) damage with or without clinical evidence of the damage, or it must result in or lead to an alteration in individual risk factors which changes the impact of subsequent exposures (e.g., dust exposures, air pollution, cigarette smoking, other environmental agents, respiratory infections). THE RESPIRATORY END POINTS This review of respiratory tract responses to a variety of different types of environmental agents has shown that a range of respiratory effects is possible in response to each of the different types of irritant

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite exposures. With the exception of effects limited to upper airway irritation (non-productive cough, hoarseness), most of these may be grouped together as obstructive lung diseases, a term that includes several different clinical syndromes: simple chronic bronchitis (mucus hypersecretion); chronic obstructive bronchitis (characterized by mucus hypersecretion and chronic airflow limitation, largely irreversible); emphysema (defined in anatomical terms as an increase in the size of the distal airspaces and destruction of their walls); and a variety of airway reactivity conditions including allergic bronchoconstriction (acute recurrent episodic reversible airflow limitation with specific airway hypersensitivity), inflammatory bronchoconstriction (acquired airway hyperresponsiveness from nonimmunogenic irritant exposures characterized by reversible airflow obstruction and nonspecific airway hypersensitivity), and pharmacologic bronchoconstriction (reversible airflow limitation without evidence of a hypersensitive subgroup of the population of exposed). As with any set of clinical syndromes, there is a degree of overlap, and classification changes as understanding the underlying mechanism improves. Simple Chronic Bronchitis Basically there are no good population data on this condition as in and of itself it is not considered to be a disabling (therefore relevant) condition. Chronic Obstructive Bronchitis and Emphysema The British hypothesis suggests that chronic bronchitis and chronic airflow limitation (by implication, emphysema) are separate parallel disease processes affecting different parts of the respiratory tract. Both were related at least to cigarette smoking and asthma was unrelated to either. The Dutch hypothesis focuses on individual susceptibility, hyperreactive airways, as key in both conditions and independent of cigarette smoking. Follow-up study suggests both are correct. Smokers who develop chronic airflow limitation (a minority) have been shown to have increased airway reactivity while both air pollutants and cigarettes produced accelerated decline in pulmonary function independent of airway reactivity. Both chronic obstructive bronchitis and emphysema have been shown to be related independently to the irritant effects of inhaled airborne dust but not to each other. Similar results are seen in response to chronic exposures to irritant gases or vapors. As in the case of cigarettes, although dose-response relationships have generally been demonstrated to both the level and the intensity of exposure, not all

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite those exposed to what appear to be comparable levels are affected. This points to a role of individual susceptibility. In turn, the key factor which makes an individual susceptible may well be the capacity of his or her airways to become reactive to inhaled materials. Allergic Bronchoconstriction Different patterns of asthmatic reactions have been noted in response to high and low molecular weight agents. The former (proteins, polysaccharides and peptides) produce specific IgE (sometimes IgG) antibodies, generally have a positive immediate skin test to extracts, and produce results in isolated immediate or biphasic (immediate and late) reactions, but generally do not show isolated late reactions. These appear not to differ in mechanism  from  asthma due to common allergens such as house dust. The latter, low molecular weight agents appear to be of two types. Some (e.g., the anhydrides or platinum salts) act as haptens and show asthma patterns similar to the high molecular weight agents. Others, best exemplified by the isocyanates, do not produce IgE in most responders. The asthma associated with isocyanates affects 5-10% of the exposed, and is associated predominantly with a late phase (isolated or part of a biphasic reaction) response to inhalation challenge studies. The asthma persists after removal in many and appears to affect atopic and non-atopic individuals equally. Inflammatory Bronchoconstriction Immunologically active substances can cause occupational asthma in some exposed workers while exposure to nonimmunogenic substances (i.e., irritants) may cause reactive airway dysfunction (RADS) or irritant induced occupational asthma in a wider population. Asthma and airway hyperresponsiveness typically occur together although they are not synonymous, so irritant-induced asthma is not necessarily caused through an acquired airway hyperreactivity mechanism. Documentation of the mechanism, however, would be strongly suggestive. Hyperresponsiveness is an amplification of the normal physiologic response to irritant stimulation. It is a characteristic of asthma, but is not always associated with overt asthma or with respiratory symptoms. It can be an inherent characteristic of the person or an acquired one, and it can be either temporary or permanent. Distribution of hyperresponsiveness in population studies is skewed, possibly bimodal. It has been hypothesized that it may lead to, or may be a predisposing factor in, subsequent chronic obstructive lung disease. This is a candidate for

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite a biologically plausible mechanism for an acute irritant exposure resulting in a postponed but long-term effect which is chronic in nature. Pharmacologic Bronchoconstriction Although not without controversy, this type of environmentally induced asthma is similar to airway reactivity in response to pharmacologic agonists. In this regard, there is a common dose-response relationship with high enough exposures causing reactions in all exposed subjects. Since these reactions are not associated with eosinophilia or nonspecific bronchial hyperreactivity, some argue they should not be considered asthma. Regardless, the causative agents are clearly associated with airway reactions such as those represented by byssinosis and the related chronic effects of exposures to cotton dust (or endotoxin). HOST FACTORS In both the examination of chronic airflow limitation and the examination of allergic asthma, less effort has been spent on objective characterization of the environmental exposures and more on delineating host factors such as the sensitization status of the individual. The preceding review, however, suggests that many respiratory irritants and toxins affect broad portions of the population. Host factors certainly interact with these agents, but it should be recognized that the following commonly discussed individual risk factors or habits play a more variable role in the non-malignant respiratory diseases than is often recognized. There is little evidence to suggest that gender or race are important risk factors in differentiating the types of respiratory tract responses to the above agents. Age, similarly, is relatively unimportant except for those of increasing age having increasing probability of experiencing a wider variety of irritant exposure events. Atopic status appears to be a risk factor for asthma due to some of the high molecular weight agents but does not appear important for many if not all of the low molecular weight agents. The other respiratory conditions do not seem to be affected by atopic status. Although nonspecific bronchial reactivity is often noted in the majority of patients with occupational asthma, it is not known whether this is a result of the exposure or a predisposing factor. Studies in red cedar asthma suggest that the increased bronchial reactivity is reduced or returns to normal after exposure ceases, suggesting that the reactivity change is a result of the exposure.80 Similar conclusions might be drawn from a recent study comparing subjects responding to cotton dust (with both byssinotic and non-byssinotic symptoms) and asymptomatic workers, which showed nonspecific bronchial reactivity most prevalent among byssinotics

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite and least prevalent in the asymptomatic subjects. However, when reactivity was examined without respect to symptoms, cumulative cotton dust level was a significant predictor of reactivity.81 Kennedy recently addressed the question of whether nonspecific bronchial reactivity was an acquired or inherent feature of respiratory reactions in persons exposed to non-immunogenic irritant agents.5 She reluctantly concluded that the question remains unanswered, although there is growing evidence that acquired increased bronchial reactivity is of likely importance. Smoking (a personal habit rather than a host factor) is well described as a risk factor for chronic obstructive bronchitis and chronic airflow limitation (or emphysema). Agents that cause these conditions most probably result in effects which are additive to those of cigarette smoking.82 The fact that all smokers do not experience the same level of risk suggests that smoking, itself, must be interacting with some other host factor in regard to these respiratory outcomes. With respect to asthma, the role of smoking is quite unclear. One hypothesis suggests that increased membrane permeability of smokers allows greater penetration of antigens. However, smoking has not been associated with work-related symptoms among those exposed to such agents as detergent enzymes83 or colophony84 while it has been noted to be related instudies of workers exposed to phthalic anhydride85 and of soy bean workers.86 In contrast, in studies of those exposed to plicatic acid or to isocyanates, asthma was mostly noted in non-smokers.87,88 CONCLUSIONS In this review a variety of materials toxic to the respiratory tract have been examined. The review was not designed to be comprehensive, yet, it was also not unduly selective. In making the selection, agents were included which are commonly considered primarily as acute respiratory irritants, those known to induce extrinsic asthma, those which are related to non-immunogenic bronchial hyperreactivity, those which are most often responsible for slowly developing chronic fibrosis or granulomatous disease, and one which is believed to cause pharmacologic bronchoconstriction. The chronic respiratory effects associated with each of the agents reviewed included several of the general types of chronic respiratory response rather than being limited to only one type of reaction. Now, as a final step in the evaluation of the agents reviewed, an attempt should be made to answer the original three general questions about pulmonary reactions. The questions and suggested answers are: Does the occurrence of an acute pulmonary reaction identify an individual at risk for long-term respiratory sequelae? Ample evidence

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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite has been provided for all of the agents reviewed that a significant portion of individuals who react acutely to short, high exposures (and even some to short, relatively low exposures) go on to develop a variety of long-term respiratory effects. The agents differ in the probability of long-term adverse outcomes, but none appear to be free of this risk. The literature reviewed does not allow identification of a minimum magnitude of acute response necessary in order for there to be long-term sequelae. If acute pulmonary reactions can identify individuals at risk for long-term sequelae, can the probability or degree of damage be predicted from  the magnitude of the acute response? The second question has generally not been studied. The fact that an association of dose is found with the acute as well as the chronic responses, provides support for the association, but not for a relationship between the magnitude of the acute response and the magnitude of the chronic response. Only in the case of the non-asthma-like isocyanate effects has the question been directly addressed. Here the acute cross-shift change in FEV1 has several times been significantly correlated with accelerated decrement in function. This association, however, is not invariant since the highly significant correlations were still under 0.5. Furthermore, the acute symptomatic response has not been a reliable predictor of accelerated functional losses. If the disease model invoked requires the acute exposure to cause acute irreversible damage one might propose that it is likely the magnitude of acute response would predict the magnitude of the chronic. However, if the model invoked is that the acute exposure resulted in or led to an alteration in individual risk factors, then it is quite likely that the magnitude of the acute and chronic responses would be unrelated. What assurance is there that the absence of an acute pulmonary reaction identifies individuals who will not develop long-term sequelae? This may be the most important question to ask and, unfortunately, the one for which no direct evidence could be found. The indirect evidence reported, however, would suggest that it would have to be an unusual disease model which would need to be invoked that could exclude the possible mechanism of change in individual risk factors so that the absence of an acute reaction would eliminate the possibility of a chronic effect related to the acute exposure. LITERATURE CITED 1. Somani SM, Babu SR. Toxicodynamics of sulfur mustard. Int J Clin Pharm Therapy Tox (1989) 27:419-435. 2. World Health Organization. 1984 report of the specialists appointed by the Secre-

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